Evidence map›Paper›PMID 34469765›Full record

ArticleLancet (London, England)2021

Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.

Philip Joseph, Gholamreza Roshandel, Peggy Gao, Prem Pais, Eva Lonn, Denis Xavier, Alvaro Avezum, Jun Zhu, Lisheng Liu, Karen Sliwa and 16 more

Abstract read
PubMed Publisher
In one paragraph

Article in Lancet (London, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
66citing papers in PubMed, 6 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

66 citing papers in PubMed, 6 syntheses or guidelines pooled it.

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  7. Low-Dose Telmisartan/Amlodipine in Essential Hypertension: A Phase III Trial.Journal of clinical hypertension (Greenwich, Conn.) · 2026
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6 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors.

Philip JosephPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Gholamreza RoshandelGolestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Peggy GaoPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Prem PaisSt John's Research Institute, Bangalore, India.
Eva LonnPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Denis XavierSt John's Research Institute, Bangalore, India; St John's Medical College, Bangalore, India.
Alvaro AvezumInternational Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.
Jun ZhuChinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Lisheng LiuChinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Karen SliwaCape Heart Institute, Department of Medicine and Cardiology, University of Cape Town, Cape Town, South Africa.
Habib GamraFattouma Bourguiba University Hospital and University of Monastir, Monastir, Tunisia.
Shrikant I BangdiwalaPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Koon TeoPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Rafael DiazEstudios Clínicos Latino América, Instituto Cardiovascular de Rosario, Rosario, Argentina.
Antonio DansUniversity of the Philippines, Manila, Philippines.
Patricio Lopez-JaramilloUniversidad de Santander, Instituto Masira, Facultad de Ciencias de la Salud, Bucaramanga, Colombia.
Dorairaj PrabhakaranPublic Health Foundation of India, Haryana, India.
Jose Maria CastellanoCentro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain; Centro Integral de Enfermedades Cardiovasculares, Hospital Universitario Monteprincipe, Grupo HM Hospitales, Madrid, Spain.
Valentin FusterZena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Anthony RodgersThe George Institute for Global Health, Sydney, NSW, Australia.
Mark D HuffmanThe George Institute for Global Health, Sydney, NSW, Australia; Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Jackie BoschPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Gilles R DagenaisUniversité Laval, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada.
Reza MalekzadehDigestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Salim YusufPopulation Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. Electronic address: yusufs@mcmaster.ca.
Polypill Trialists' Collaboration

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundIn randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown.

methodsWe did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies.

findingsThree large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53-0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38-0·70), revascularisation (0·54, 0·36-0·80), stroke (0·59, 0·45-0·78), and cardiovascular death (0·65, 0·52-0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001).

interpretationFixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors.

fundingPopulation Health Research Institute.

Indexed as

Drug Therapy, CombinationMeta-Analysis as TopicPrimary PreventionAspirinBlood PressureCardiovascular DiseasesFemaleGastrointestinal HemorrhageHumansMaleMiddle AgedMyocardial InfarctionPlatelet Aggregation InhibitorsRandomized Controlled Trials as TopicStrokeAspirinPlatelet Aggregation Inhibitors

Identifiers

PMID34469765

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.